A limitation of traditional medical treatment using therapeutic or diagnostic agents is the lack of specificity. Indeed, in most cases, only a small fraction of the administered dose of therapeutic or diagnostic agent reaches the site of interest, while the rest of the agent is distributed throughout the body. This unavoidable distribution into healthy organs and tissue limits the agent's amount that can be administered to a patient, and in turn prevents the agent from achieving the therapeutic or diagnostic effect it is capable of.
The need for site-specific agent delivery vehicles that would not only increase the amount of agent reaching the intended site but would also decrease the amount being delivered to other, healthy parts of the body has been recognized for a long time, in particular for toxic chemotherapeutic drugs. Such vehicles capable of reducing or even eliminating side effects would make the treatment considerably less toxic and more effective. Liposomes have a decade-long clinical presence as nanoscale delivery vehicles for therapeutic and diagnostic agents.
The biggest challenge facing any agent delivery vehicle is to allow the complete release of the encapsulated agents from the vehicle specifically at the diseased site and at a controllable rate.
Moreover, the use of liposomes as delivery vehicles for nanoparticles is still in the preclinical development stages, in particular in the context of externally activable nanoparticles (Al-Jamal, W. T. et al., Nanomedicine, 2007, 2:85-98).
The preparation of liposomes formulated with PEG-lipids containing either a fusogenic or a pH-sensitive lipid to promote destabilization of endosomal membranes and favor quantum dots (QD) cytoplasmic release has been described in vitro (Sigot et al., Bioconjugate Chem. 2010, 21:1465-1472). PEG-lipid dissociation from the liposome can be facilitated by incorporating fusogenic PEG-lipids with a short acyl chain promoting transfer from the liposome to the bilayer within minutes. Alternatively, PEG-lipids can be intracellularly released by adding a cleavable, pH-sensitive PEG analogue in which the polymer moiety is cleaved from the liposome surface upon exposure to the acidic environment of certain endosomal compartments. While such “spontaneous” release can be advantageous (especially for the treatment of distant metastases), since it relies solely on the local environment, liposome content release can still be slow and may not occur at all if the environment is not optimal. The precise control of the liposome's content release is therefore not possible with such liposomes.
The preparation of liposomes comprising a photosensitizer has further been described (US 2010/0233224). The photosensitizer is capable of oxidizing the unsaturated phospholipids of the liposome's membrane when exposed to light and oxygen through peroxidation of lipid chains. Photo-oxidation of liposomes can be triggered to release their load on demand and rapidly through an external light stimulus. The oxidation is responsible for the liposome's membrane failure and for the subsequent release of the liposome's content. However, such a light source can only be used where the targeted tissue is superficially accessible. Liposomes incorporated into deeper tissues cannot be stimulated by light. Liposomes comprising a photosensitizer can therefore not be used to deliver nanoparticles to deep organs or structures of the human body.
Laser activable hollow metal nanostructures have also been used in the past as a means to trigger the permeabilization of the liposome's membrane into which they were encapsulated in order to allow the selective release of a drug (WO 2009/097480).
US 2009004258 describes thermosensitive liposomes encapsulating paramagnetic iron oxide nanoparticles and drugs, the paramagnetic iron oxide nanoparticles allowing the specific or selective release of drugs in a targeted environment under activation by an alternative magnetic field. These liposomes however are not permeable to the encapsulated nanoparticles.
The inventors now herein provide advantageous systems allowing the safe in vivo delivery, and controlled and efficient release, of nanoparticles in a subject.
These systems in particular allow the delivery and release of externally activable nanoparticles in deep structures of the human body. Examples of efficient activable nanoparticles, usable as diagnostic and/or therapeutic tools, were described by the inventors in WO2007/118884, WO 2009/147214 and WO2011/003999.